An improved understanding of the mechanisms leading to COPD pathogenesis, as well as novel targets for therapeutic intervention, are needed. Peroxisome proliferator-activating receptor (PPAR)-? has been previously shown to be capable of regulating inflammatory responses in multiple organs. PPAR?-activating ligands, the thaizoladinediones (TZDs), are FDA approved. Regulation of PPAR? activity, using these drugs, is associated with reduced morbidity in animal models of inflammatory lung disease. However, the importance of this molecule in lung epithelial cells and in COPD has not been determined. We find increased expression of PPAR? in human COPD tissues, and in epithelial cells from smokers. In lung epithelial cells, PPAR? can regulate genes associated with lung tissue remodeling. We have previously reported that deficiency in PPAR? specifically within epithelial cells leads to a defect in lung maturation resulting in variation in lung structure and function in mice. Here, we present data indicating that mice deficient in lung epithelial cell PPAR? also show increased susceptibility to the development of emphysema in response to chronic cigarette smoke exposure. This is associated with an increase in the accumulation of inflammatory macrophages, the critical effector cell for emphysema pathogenesis, and increased lung chemokine gene expression. We present preliminary data indicating that activating PPAR? using TZDs in mice reduces smoke-related inflammation and chemokine expression, critical cellular and molecular intermediate phenotypes in this pre-clinical model of COPD. In vivo, epithelial cells are highly responsive to PPAR? regulators, and exposure to cigarette smoke increased PPAR? expression, supporting the contributions of epithelial cell PPAR? in regulating smoke-induced inflammation. In total, these data support a role for PPAR? as a susceptibility factor in COPD with potential as a target for disease-modifying therapy. We hypothesize that reduced PPAR? activity increases susceptibility to smoke- induced lung injury and that exogenous activation of PPAR? using TZDs will reduce COPD morbidity. We propose that epithelial PPAR? functions specifically to regulate the expression of epithelial-derived chemokines involved in inflammatory cell recruitment, macrophage activation and tissue destruction in response to chronic smoke exposure. In an effort to test these hypotheses we propose to: 1) Define the cellular and molecular mechanisms leading to increased susceptibility to cigarette smoke-induced emphysema in the absence of lung epithelial cell PPAR? function in mice. 2) Evaluate PPAR?-activating therapeutic ligands for the ability to limit emphysema pathology in mice exposed to cigarette smoke. 3) Investigate the ability of PPAR? activation to suppress smoke-induced lung epithelial cell chemokine expression in human cells and in COPD subjects as part of a phase II clinical trial. In total, these experiments will test the mechanistic role of PPAR? in a preclinical model of COPD, specifically address the role of epithelial cell PPAR? in regulating disease pathogenesis, and evaluate relevance and potential therapeutic benefits of PPAR? activation in humans with COPD.